Methods for Treating MS Using Pyrimidine and Pyridine Compounds with BTK Inhibitory Activity

ABSTRACT

The present invention provides methods of treating MS using pyrimidine and pyridine compounds which are inhibitors of Bruton&#39;s tyrosine kinase (BTK).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/352,657, filed on Nov. 16, 2016. This application claims the benefitof U.S. provisional application No. 62/256,199, filed on Nov. 17, 2015.The content of each of these applications is hereby incorporated byreference in their entirety.

BACKGROUND OF THE INVENTION Field of the Invention

The invention relates to a series of pyrimidine and pyridine compoundsthat are useful as therapeutics in the treatment of multiple sclerosis(MS) in mammals. More particularly, embodiments of the present inventiondescribe irreversible kinase inhibitors including, but not limited to,inhibitors of Bruton's tyrosine kinase (hereinafter referred to as:“BTK”). Methods for the preparation of the aforementioned compounds aredisclosed in addition to the incorporation of these compounds intopharmaceutical compositions that include the same.

Discussion of the Background

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a wide variety of signaltransduction processes within the cell (Hardie, G. and Hanks, S. (1995)The Protein Kinase Facts Book. I and II, Academic Press, San Diego,Calif.). The kinases may be categorized into families by the substratesthey phosphorylate (e.g., protein-tyrosine, protein-serine/threonine,lipids, etc.). Sequence motifs have been identified that generallycorrespond to each of these kinase families (e.g., Hanks, S. K., Hunter,T., FASEB J., 9:576-596 (1995); Knighton, et al., Science, 253:407-414(1991); Hiles, et al., Cell, 70:419-429 (1992); Kunz, et al., Cell,73:585-596 (1993); Garcia-Bustos, et al., EMBO J., 13:2352-2361 (1994)).

Protein kinases may be characterized by their regulation mechanisms.These mechanisms include, for example, autophosphorylation,transphosphorylation by other kinases, protein-protein interactions,protein-lipid interactions, and protein-polynucleotide interactions. Anindividual protein kinase may be regulated by more than one mechanism.

Kinases regulate many different cell processes including, but notlimited to, proliferation, differentiation, apoptosis, motility,transcription, translation and other signalling processes, by addingphosphate groups to target proteins. These phosphorylation events act asmolecular on/off switches that can modulate or regulate the targetprotein biological function. Phosphorylation of target proteins occursin response to a variety of extracellular signals (hormones,neurotransmitters, growth and differentiation factors, etc.), cell cycleevents, environmental or nutritional stresses, etc. The appropriateprotein kinase functions in signalling pathways to activate orinactivate (either directly or indirectly), for example, a metabolicenzyme, regulatory protein, receptor, cytoskeletal protein, ion channelor pump, or transcription factor. Uncontrolled signalling due todefective control of protein phosphorylation has been implicated in anumber of diseases, including, for example, inflammation, cancer,allergy/asthma, diseases and conditions of the immune system, diseasesand conditions of the central nervous system, and angiogenesis.

BTK, a member of the Tec family of non-receptor tyrosine kinases, is asignaling enzyme expressed in all hematopoietic cells types except Tlymphocytes and natural killer cells. BTK plays a well documented rolein the B-cell signaling pathway linking cell surface B-cell receptorstimulation to downstream intracellular responses. BTK is also aregulator of B-cell development, activation, signaling, and survival(Kurosaki, Curr Op Imm, 2000, 276-281; Schaeffer and Schwartzberg, CurrOp Imm 2000, 282-288). In addition, BTK exerts a physiological effectthrough other hematopoietic cell signaling pathways, e.g., Toll likereceptor (TLR) and cytokine receptor-mediated TNF-a production inmacrophages, IgE receptor (FcepsilonRl) signaling in Mast cells,inhibition of Fas/APO-1 apoptotic signaling in B-lineage lymphoid cells,and collagen-stimulated platelet aggregation. BTK has an ATP-bindingpocket with high similarity to Src-family kinases, such aslymphocyte-specific protein tyrosine kinase (Lck) and Lyn. Comparing BTKto other kinases one finds a conserved cysteine residue, Cys-481, in 11of 491 kinases, specifically members of the Tec and EGFR (epidermalgrowth factor receptor) kinase families.

BTK plays important roles in the development, differentiation,activation and proliferation of B cells, as well as their antibody andcytokine generation. In addition, Btk plays a central role in otherimmunological processes such as cytokine production by neutrophils, mastcells and monocytes, degranulation of neutrophils and mast cells as wellas differentiation/activation of osteoclasts. B-cell activation, breakof tolerance and auto-antibody production, on one hand and theproinflammatory milieu originated from exacerbated activation ofmonocytes, neutrophils and mast cells, on the other hand, are crucial inthe etiology of autoimmune diseases, including (but not limited to)rheumatoid arthritis and systemic lupus erythematosus.

Reversible kinase inhibitors have been developed into therapeuticcompounds. These reversible inhibitors, however, have decideddisadvantages. Many reversible inhibitors of kinases interact with theATP-binding site. Given the structure of the ATP-binding sites arehighly conserved among kinases, it has been difficult to develop areversible inhibitor that selectively inhibits a desired (i.e., target)kinase. Moreover, given that many reversible kinase inhibitors readilydissociate from their target polypeptide(s), maintaining inhibition overextended periods of time can be difficult. When using reversible kinaseinhibitors as therapeutics, therefore, often times near toxic dosagesand/or frequent dosing is required to achieve the intended biologicaleffect.

What is needed, therefore, are irreversible kinase inhibitors thatcovalently bind to their target polypeptide(s) without (substantially)binding to off-target polypeptides and, thereby, exerting undesirableoff-target effects.

SUMMARY OF THE INVENTION

The present invention is directed towards compounds of the formulaepresented herein for the treatment and/or prophylaxis of multiplesclerosis (MS), including relapsing MS (RMS), relapsing-remitting MS(RRMS), progressive MS (PMS), secondary-progressive MS (SPMS),primary-progressive MS (PPMS), and progressive-relapsing MS (PRMS).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 (a) shows prophylactic treatment with (1) delayed onset andreduced disease severity in SJL-EAE.

FIG. 1 (b) shows maximum clinical score at peak for prophylactictreatment with (1) delayed onset and reduced disease severity inSJL-EAE.

FIG. 1 (c) shows disease onset for prophylactic treatment with (1)delayed onset and reduced disease severity in SJL-EAE.

FIG. 1 (d) shows cumulative clinical score for prophylactic treatmentwith (1) delayed onset and reduced disease severity in SJL-EAE.

FIG. 2 (a) shows time to first relapse of prophylactic treatment with(1) reduced relapse activity in SJL-EAE.

FIG. 2 (b) shows total number of relapses for prophylactic treatmentwith (1) reduced relapse activity in SJL-EAE

FIG. 2 (c) shows summary of prophylactic treatment with (1) reducedrelapse activity in SJL-EAE

FIG. 3 (a) shows therapeutic treatment with (1) reduced disease severityin SJL-EAE.

FIG. 3 (b) shows the cumulative EAE score for therapeutic treatment with(1) reduced disease severity in SJL-EAE.

FIG. 4 (a) shows therapeutic treatment with (1) reduced relapse activityin SJL-EAE.

FIG. 4 (b) shows the total number of relapses for therapeutic treatmentwith (1) reduced relapse activity in SJL-EAE.

FIG. 4 (c) shows the summary of therapeutic treatment with (1) reducedrelapse activity in SJL-EAE.

FIG. 5 shows the summary table of clinical score data: compound (1).

FIG. 6 (a) shows BTK occupancy after prophylactic treatment with (1) (24hours post treatment) after first dose.

FIG. 6 (b) shows BTK occupancy after prophylactic treatment with (1) (24hours post treatment) after last dose.

FIG. 7 (a) shows BTK occupancy after first (1) dose (therapeutic study).

FIG. 7 (b) shows BTK blood concentrations after first (1) dose(therapeutic study).

FIG. 8 shows BTK occupancy after therapeutic treatment with (1) (24hours post treatment).

FIG. 9 (a) shows the compound (2) significantly decreases diseaseseverity when administered prophylactically.

FIG. 9 (b) shows the cumulative EAE score for the compound (2)significantly decreases disease severity when administeredprophylactically.

FIG. 10 (a) shows the compound (2) decreased incidence of disease andrelapses in EAE model.

FIG. 10 (b) shows the summary of the compound (2) decreased incidence ofdisease and relapses in EAE model.

FIG. 11 shows the compound (2) PK/PD experimental design.

FIG. 12 (a) shows the compound (2) BTK Occupancy at 2 hr post-dose(measured by streptavidin capture MSD assay).

FIG. 12 (b) shows the compound (2) BTK Occupancy at 24 hr post-dose(measured by streptavidin capture MSD assay).

FIG. 13 shows the compound (2) free plasma concentrations at 2 hr and 24hr post-dose (measured by dried blood spot analysis).

FIG. 14 (a) shows the therapeutic dosing with compound (2) reduceddisease severity in SJL-EAE.

FIG. 14 (b) shows the cumulative EAE score of the therapeutic dosingwith compound (2) reduced disease severity in SJL-EAE.

FIG. 15 (a) shows the therapeutic dosing with Compound (2) prolongedtime to first relapse and decreased relapses.

FIG. 15 (b) shows the number of relapses for the therapeutic dosing withCompound (2).

FIG. 15 (c) shows the summary of the therapeutic dosing with Compound(2) prolonged time to first relapse and decreased relapses.

FIG. 16 shows the Compound (2) experimental design.

FIG. 17 (a) shows the Compound (2) BTK Occupancy at 2 hr Post-dose(measured by streptavidin capture MSD assay).

FIG. 17 (b) shows the Compound (2) BTK Occupancy at 24 hr Post-dose(measured by streptavidin capture MSD assay).

FIG. 18 (a) shows the therapeutic dosing with Compound (2) reduceddisease severity in SJL-EAE.

FIG. 18 (b) shows the cumulative score for the therapeutic dosing withCompound (2) reduced disease severity in SJL-EAE.

FIG. 19 (a) shows the therapeutic dosing with Compound (2) reduced thenumber of relapses.

FIG. 19 (b) shows the summary of the therapeutic dosing with Compound(2) reduced.

FIG. 20 (a) shows the semi-therapeutic dosing with Compound (2) reduceddisease severity in SJL-EAE.

FIG. 20 (b) shows the cumulative score for the semi-therapeutic dosingwith Compound (2) reduced disease severity in SJL-EAE.

FIG. 21 (a) shows time to first relapse for the therapeutic dosing withCompound (2) reduced.

FIG. 21 (b) shows the number of relapses for the therapeutic dosing withCompound (2) reduced.

FIG. 21 (c) shows the summary of the therapeutic dosing with Compound(2) reduced.

Throughout the specification and the figures, the terms compound (1) andcompound (A250) are used interchangeably. Throughout the specificationand the figures, the terms compound (2) and compound (A225) are usedinterchangeably.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a series of novel pyrimidine and pyridinekinase inhibitors. In some embodiments said kinase inhibitors areirreversible inhibitors of tyrosine kinases. In preferred embodiments,said irreversible kinase inhibitors inhibit BTK. While it is notintended that the compounds described by the present invention belimited to any specific mechanism of action, in some embodiments saidirreversible kinase inhibitors exert a physiological effect by forming acovalent bond with Cys 481 in BTK. Significantly, this Cys 481 in BTKfinds homologs in other kinases. Embodiments of the present inventionalso described methods for synthesizing said irreversible inhibitors,methods for using said irreversible inhibitors in the treatment ofdiseases (including neurodegenerative diseases). Further described arepharmaceutical formulations that include an irreversible kinaseinhibitor including pharmaceutically acceptable salts, solvates orprodrugs thereof, that are kinase inhibitors and useful in the treatmentof the above mentioned diseases.

In one aspect, the invention provides a method for the treatment and/orprophylaxis of multiple sclerosis (MS), including relapsing MS (RMS),relapsing-remitting MS (RRMS), progressive MS (PMS),secondary-progressive MS (SPMS), primary-progressive MS (PPMS), andprogressive-relapsing MS (PRMS), comprising administering to a subject acompound of Formula (I):

-   -   in which:    -   X denotes CH or N,    -   R¹ denotes NH₂, CONH₂ or H,    -   R² denotes Hal, Ar¹ or Het¹,    -   R³ denotes NR⁵[C(R⁵)₂]_(n)Het², NR⁵[C(R⁵)₂]_(n)Cyc, Het²,        O[C(R⁵)₂]_(n)Ar², NR⁵[C(R⁵)₂]_(n)Ar², O[C(R⁵)₂]_(n)Het²,        NR⁵(CH₂)_(p)NR⁵R⁶, O(CH₂)_(p)NR⁵R⁶ or NR⁵(CH₂)_(p)CR⁷R⁸NR⁵R⁶,    -   R⁴ denotes H, CH₃ or NH₂,    -   R⁵ denotes H or alkyl having 1, 2, 3 or 4 C atoms,    -   R⁶ N(R⁵)₂CH₂CH═CHCONH, Het³CH₂CH═CHCONH, CH₂═CHCONH(CH₂)_(n),        Het⁴(CH₂)_(n)COHet³-diyl-CH₂CH═CHCONH, HC≡CCO, CH₃CCCO,        CH₂═CH—CO, CH₂═C(CH₃)CONH, CH₃CH═CHCONH(CH₂)_(n),        N≡CCR⁷R⁸CONH(CH₂)_(n), Het⁴NH(CH₂)_(p)COHet³-diyl-CH₂CH═CHCONH,        Het⁴(CH₂)_(p)CONH(CH₂CH₂O)_(p)(CH₂)_(p)COHet³-diyl-CH₂CH═CHCONH,        CH₂═CHSO₂, ACH═CHCO, CH₃CH═CHCO,        Het⁴(CH₂)_(p)CONH(CH₂)_(p)Het³-diyl-CH₂CH═CHCONH, Ar³CH═CHSO₂,        CH₂═CHSO₂NH or N(R⁵)CH₂CH═CHCO,    -   R⁷, R⁸ denote together alkylene having 2, 3, 4, or 5 C atoms,    -   Ar¹ denotes phenyl or naphthyl, each of which is unsubstituted        or mono-, di- or trisubstituted by R⁶, Hal, (CH₂)_(n)NH₂,        CONHAr³, (CH₂)nNHCOA, O(CH₂)_(n)Ar³, OCyc, A, COHet³, OA and/or        OHet³ (CH₂),    -   Ar² denotes phenyl, naphthyl or pyridyl each of which is        unsubstituted or mono-, di- or trisubstituted by R⁶, Hal, OAr³,        (CH₂)_(n)NH₂, (CH₂)_(n)NHCOA and/or Het³,    -   Ar³ denotes phenyl, which is unsubstituted or mono-, di- or        trisubstituted by OH, OA, Hal, CN and/or A,    -   Het¹ denotes a mono-or bicyclic saturated, unsaturated or        aromatic heterocycle having 1 to 4 N, O and/or S atoms, which        may be unsubstituted or mono-, di- or trisubstituted by R⁶,        O(CH₂)_(n)Ar³ and/or (CH₂)_(n)Ar³,    -   Het² denotes a mono-or bicyclic saturated heterocycle having 1        to 4 N, O and/or S atoms, which may be unsubstituted or mono-,        di- or trisubstituted by R⁶, Het³, CycSO₂, OH, Hal, COOH, OA,        COA, COHet³, CycCO, SO₂ and/or ═O,    -   Het³ denotes a monocyclic unsaturated, saturated or aromatic        heterocycle having 1 to 4 N, O and/or S atoms, which may be        unsubstituted or mono-, di- or trisubstituted by Hal, A and/or        ═O,    -   Het⁴ denotes a bi- or tricyclic unsaturated, saturated or        aromatic heterocycle having 1 to 4 N, O and/or S atoms, which        may be unsubstituted or mono-, di-, tri- or tetrasubstituted by        A, NO2, Hal and/or ═O,    -   Cyc denotes cyclic alkyl having 3, 4, 5 or 6 C atoms, which is        unsubstituted, monosubstituted or disubstituted by R⁶ and/or OH        and which may comprise a double bond,    -   A denotes unbranched or branched alkyl having 1-10 C atoms, in        which 1-7 H atoms may be replaced by F and/or Cl and/or in which        one or two non-adjacent CH₂ and/or CH-groups may be replaced by        O, NH and/or by N,    -   Hal denotes F, Cl, Br or I,    -   n denotes 0, 1, 2, 3 or 4,    -   p denotes 1, 2, 3, 4, 5 or 6,    -   and pharmaceutically usable salts, tautomers and stereoisomers        thereof, including mixtures thereof in all ratios.

In general, all residues which occur more than once may be identical ordifferent, i.e. are independent of one another. In other embodiments,the residues and parameters have the meanings indicated for the Formula(I), unless expressly indicated otherwise.

In certain embodiments, Het¹ denotes piperidinyl, piperazinyl,pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl,benzo-1,3-dioxolyl, indazolyl, azabicyclo[3.2.1]octyl,azabicyclo[2.2.2]octyl, imidazolidinyl, azetidinyl, azepanyl,benzo-2,1,3-thiadiazolyl, tetrahydrofuryl, dioxolanyl,tetrahydrothienyl, dihydropyrrolyl, tetrahydroimidazolyl,dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl, dihydropyridylor dihydrobenzodioxinyl, each of which is unsubstituted or mono-, di- ortrisubstituted by R⁶, O(CH₂)_(n)Ar³ and/or (CH₂)_(n)Ar³.

In certain embodiments, Het¹ denotes pyrazolyl, pyridyl, pyrimidinyl,dihydropyridyl or dihydrobenzodioxinyl, each of which is unsubstitutedor mono-, di- or trisubstituted by R⁶, O(CH₂)_(n)Ar³ and/or(CH₂)_(n)Ar³.

In certain embodiments, Het² denotes piperidinyl, piperazinyl,pyrrolidinyl, morpholinyl, azabicyclo[3.2.1]octyl,azabicyclo[2.2.2]octyl, 2,7-diazaspiro[3.5]nonyl,2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[4.4]nonyl,3-azabicylo[3.1.0]hexyl, 2-azaspiro[3.3]heptyl, 6-azaspiro[3.4]octyl,7-azaspiro[3.5]nonyl, 5-azaspiro[3.5]nonyl, imidazolidinyl, azetidinyl,azepanyl, tetrahydrofuryl, dioxolanyl, tetrahydrothienyl,tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydropyridyl, each ofwhich is unsubstituted or mono-, di- or trisubstituted by R⁶, Het³,CycSO₂, OH, OA, COA, COHet³, CycCO, SO₂ and/or ═O.

In certain embodiments, Het³ denotes piperidinyl, piperazinyl,pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,pyridazinyl, pyrazinyl, imidazolidinyl, azetidinyl, azepanyl,tetrahydrofuryl, dioxolanyl, tetrahydrothienyl, dihydropyrrolyl,tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl,tetrahydropyridyl or dihydropyridyl, each of which may be unsubstitutedor mono-, di- or trisubstituted by Hal, A and/or ═O.

In certain embodiments, Het³ denotes piperidinyl, pyrrolidinyl,morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl,pyrimidinyl, dihydropyrrolyl, dihydropyrazolyl or dihydropyridyl, eachof which may be unsubstituted or mono-, di- or trisubstituted by Hal, Aand/or ═O.

In certain embodiments, Het⁴ denotes hexahydrothieno[3,4-d]imidazolyl,benzo[c][1,2,5] oxadiazolyl or5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-uidyl, each ofwhich may be unsubstituted or mono-, di-, tri- or tetrasubstituted by A,NO₂, Hal and/or ═O.

In certain embodiments,

-   -   X denotes CH or N,    -   R¹ denotes NH₂, CONH₂ or H,    -   R² denotes Hal, Ar¹ or Het¹,    -   R³ denotes NR⁵[C(R⁵)₂]_(n)Het², NR⁵[C(R⁵)₂]_(n)Cyc, Het²,        O[C(R⁵)₂]_(n)Ar², NR⁵[C(R⁵)₂]_(n)Ar², O[C(R⁵)₂]_(n)Het²,        NR⁵(CH₂)_(p)NR⁵R⁶, O(CH₂)_(p)NR⁵R⁶ or NR⁵(CH₂)_(p)CR⁷R⁸NR⁵R⁶,    -   R⁴ denotes H,    -   R⁵ denotes H or alkyl having 1, 2, 3 or 4 C atoms,    -   R⁶ N(R⁵)₂CH₂CH═CHCONH, Het³CH₂CH═CHCONH, CH₂═CHCONH(CH₂)_(n),        Het⁴(CH₂)_(n)COHet³-diyl-CH₂CH═CHCONH, HC≡CCO, CH₃C≡CCO,        CH₂═CH—CO, CH₂═C(CH₃)CONH, CH₃CH═CHCONH(CH₂)_(n),        N≡CCR⁷R⁸CONH(CH₂)_(n), Het⁴NH(CH₂)_(p)COHet³-diyl-CH₂CH═CHCONH,        Het⁴(CH₂)_(p)CONH(CH₂CH₂O)_(p)(CH₂)_(p)COHet³-diyl-CH₂CH═CHCONH,        CH₂═CHSO₂, ACH═CHCO, CH₃CH═CHCO,        Het⁴(CH₂)_(p)CONH(CH₂)_(p)Het³-diyl-CH₂CH═CHCONH, Ar³CH═CHSO₂,        CH₂═CHSO₂NH or N(R⁵)CH₂CH═CHCO,    -   R⁷, R⁸ denote together alkylene having 2, 3, 4, or 5 C atoms,    -   Ar¹ denotes phenyl or naphthyl, each of which is unsubstituted        or mono-, di- or trisubstituted by R⁶, Hal, (CH₂)_(n)NH₂,        CONHAr³, (CH₂)_(n)NHCOA, O(CH₂)_(n)Ar³, OCyc, A, COHet³, OA        and/or OHet³ (CH₂),    -   Ar² denotes phenyl or naphthyl, each of which is unsubstituted        or mono-, di- or trisubstituted by R⁶, Hal, OAr³, (CH₂)_(n)NH₂,        (CH₂)_(n)NHCOA and/or Het³,    -   Ar³ denotes phenyl, which is unsubstituted or mono-, di- or        trisubstituted by OH, OA, Hal, CN and/or A,    -   Het¹ denotes piperidinyl, piperazinyl, pyrrolidinyl,        morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,        oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,        pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,        pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl,        benzo-1,3-dioxolyl, indazolyl, azabicyclo[3.2.1]octyl,        aza-bicyclo[2.2.2]octyl, imidazolidinyl, azetidinyl, azepanyl,        benzo-2,1,3-thiadiazolyl, tetrahydrofuryl, dioxolanyl,        tetrahydrothienyl, dihydro-pyrrolyl, tetrahydroimidazolyl,        dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl,        dihydropyridyl or dihydrobenzodioxinyl, each of which is        unsubstituted or mono-, di- or trisubstituted by R⁶,        O(CH₂)_(n)Ar³ and/or (CH₂)_(n)Ar³,    -   Het² denotes piperidinyl, piperazinyl, pyrrolidinyl,        morpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[2.2.2]octyl,        2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[4.5]decyl,        2,7-diazaspiro[4.4]nonyl, 3-azabicylo[3.1.0]hexyl,        2-azaspiro[3.3]heptyl, 6-azaspiro[3.4]octyl,        7-azaspiro[3.5]nonyl, 5-azaspiro[3.5]nonyl, imidazolidinyl,        azetidinyl, azepanyl, tetrahydrofuryl, dioxolanyl,        tetrahydrothienyl, tetrahydroimidazolyl, tetrahydropyrazolyl,        tetrahydropyridyl, each of which is unsubstituted or mono-, di-        or trisubstituted by R⁶, Het³, CycSO₂, OH, OA, COA, COHet³,        CycCO, SO₂ and/or ═O,    -   Het³ denotes piperidinyl, piperazinyl, pyrrolidinyl,        morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,        oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,        pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,        pyridazinyl, pyrazinyl, imidazolidinyl, azetidinyl, azepanyl,        tetrahydrofuryl, dioxolanyl, tetrahydrothienyl, dihydropyrrolyl,        tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl,        tetrahydropyridyl or dihydropyridyl, each of which may be        unsubstituted or mono-, di- or trisubstituted by Hal, A and/or        ═O,    -   Het⁴ denotes hexahydrothieno[3,4-d]imidazolyl,        benzo[c][1,2,5]oxadiazolyl or        5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-uidyl, each        of which may be unsubstituted or mono-, di-, tri- or        tetrasubstituted by A, NO₂, Hal and/or ═O,    -   Cy c denotes cyclic alkyl having 3, 4, 5 or 6 C atoms, which is        unsubstituted or monosubstituted by R⁶ and which may comprise a        double bond,    -   A denotes unbranched or branched alkyl having 1-10 C atoms, in        which 1-7 H atoms may be replaced by F and/or Cl and/or in which        one or two non-adjacent CH₂ and/or CH-groups may be replaced by        O, NH and/or by N,    -   Hal denotes F, Cl, Br or I,    -   n denotes 0, 1, 2, 3 or 4,    -   p denotes 1, 2, 3, 4, 5 or 6.

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of multiple sclerosis (MS), includingrelapsing MS (RMS), relapsing-remitting MS (RRMS), progressive MS (PMS),secondary-progressive MS (SPMS), primary-progressive MS (PPMS), andprogressive-relapsing MS (PRMS), comprising administering to a subject acompound of Formula (II):

and pharmaceutically acceptable salts, solvates, solvates of salts, orprodrugs thereof, wherein:

X is H or CH₃ or NH₂,

Y is H, Hal or is absent,

B is N or CH,

E is NH₂ or H,

W is NR, O or a cyclic amine,

Z is, independently, CH₂, CH₃, CH₂—CH₂, CH—CH₂, H, NH or is absent,

“linker” is (CH₂)_(n), wherein: n is 1, 2 or 3or an optionallysubstituted group selected from a phenyl ring, an aryl ring, heteroarylring, branched or unbranched alkyl group, a 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, or oxygen, a 4-7 membered saturated or partially unsaturatedheterocycle having 1-3 heteroatoms independently selected from nitrogen,or oxygen, or a 7-10 membered bicyclic saturated or partiallyunsaturated heterocyclic ring having 1-5 heteroatoms independentlyselected from nitrogen, or oxygen, or a 7-10 membered bicyclic saturatedor partially unsaturated heterocyclic ring having 1-5 heteroatomsattached to a hetero saturated ring. Linkers may also be cycloalkanesoptionally substituted by heteroatoms (independently selected fromnitrogen, or oxygen), cycloalkanes optionally substituted with —NH orOH, fused or bridged rings or optionally substituted spirocyclic ringsthat optionally contain heteroatoms,

A is a mono- or bicyclic aromatic homo- or heterocycle having 0, 1, 2, 3or 4 N, and/or O atoms and 5, 6, 7, 8, 9, or 10 skeleton C atoms, whichmay be unsubstituted or, independently of one another, mono-, di- ortrisubstituted by Hal, OH or OR,

Hal is F, Cl, Br or I,

R is independently hydrogen, oxygen or an optionally substituted groupselected from C₁₋₆ linear or cyclic aliphatic, benzyl, phenyl, a phenylgroup optionally substituted with 1, 2 or 3 O atoms, a 4-7 memberedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or a 5-6 membered monocyclic heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, or oxygen or amono- or bicyclic aromatic homo- or heterocycle having 0, 1, 2, 3 or 4N, O atoms and 5, 6, 7, or 8 C skeleton atoms, which may beunsubstituted or, independently of one another, mono-, di- ortrisubstituted by Hal, A, OH, NH₂, nitrile, and/or CH(Hal)₃ or is anunbranched or branched linear alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 Catoms, in which one or two CH₂ groups may be replaced by an O atomand/or by an —NH—, —CO—, —NHCOO—, —NHCONH—, —CONH—, —NHCO— or —CH═CH—group, and in which 1-3 H atoms may be replaced by Hal,

R^(q) is selected from -R, -A, halogen, —OR, —O(CH₂)_(r)OR, —R(NH),—NO₂, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)NR₂, —NRSO₂R, or—N(R)₂,

r is 1-4,

n is 0-4, and

Q is an electrophilic group such as those listed in Table 1 wherein saidelectrophilic groups may further comprise a warhead.

As used herein the term “warhead” refers to a part, functional group orsubstituent of the compounds as claimed in the present invention,wherein, said part, functional group or substituent covalently binds toan amino acid (such as cysteine, lysine, or any other amino acid, eithernative or modified, that can form said covalent bond) that is present,for example, in the binding region within a given ligand wherein saidwarhead binds with said ligand, wherein the covalent binding betweensaid warhead and the binding region of said target protein occurs underconditions wherein a physiological function of said protein isirreversibly inhibited.

While it is not intended that the present invention be limited to aspecific group for substituent Q, as set out in Formula (II) above, incertain embodiments substituent Q is selected from the groups set out inTable 1. All compounds, in Table 1, appearing within a box are not“warheads” as defined above.

TABLE 1

 

 

 

 

 

 

 

 

 

wherein, “

” denotes the bonding point of Q to Z in Formula (II).

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of multiple sclerosis (MS), includingrelapsing MS (RMS), relapsing-remitting MS (RRMS), progressive MS (PMS),secondary-progressive MS (SPMS), primary-progressive MS (PPMS), andprogressive-relapsing MS (PRMS), comprising administering to a subject acompound of Formula (III):

and pharmaceutically acceptable salts, solvates, solvates of salts, orprodrugs thereof, wherein:

X is O or NH,

Y is N or CH,

W is H, NH₂ or CONH₂,

Q is H or NH₂,

R¹ is L¹-R⁴-L²-R⁵,

R² is M¹-S⁴-M²-S⁵

L¹ is a single bond, methylene, or cyclic A which may be mono- ordisubstituted with N or NH₂,

R⁴ is Ar, A or cyclic A which may be mono- or disubstituted with N, —O—or Hal,

R⁵ is Ar, A or cyclic A which may be mono- or disubstituted with N, —O—or Hal or is absent. In preferred embodiments, R⁵ is selected from thegroup consisting of 2-fluoropyridine, 1-methylpyridin-2(1H)-one and2-chloropyridine,

L² is H, —O—, substituted or unsubstituted C₁-C₄alkyl, substituted orunsubstituted C₁-C₄heteroalkyl, C₁-C₆alkoxyalkyl, C₁-C₈alkylaminoalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₄alkyl(aryl), C₁-C₄alkyl(heteroaryl),C₁-C₄alky(C₃-C₈cycloalkyl), or C₁-C₄alkyl(C₂-C₈ heterocycloalkyl). Insome embodiments, L² is —CH₂—O—(C₁-C₃alkyl), —CH₂—N(C₁-C₃alkyl)₂,C₁-C₄alkyl(phenyl), or C₁-C₄alkyl (5- or 6-membered heteroaryl). In someembodiments L² is -A-. In some embodiments L² is absent. In preferredembodiments of the present invention L² is selected from the groupconsisting of but-3-en-2-one, propan-2-one,(E)-5-(dimethylamino)pent-3-en-2-one, (E)-pent-3-en-2-one,pent-3-yn-2-one, 1-chloropropan-2-one, (methylsulfonyl)ethane,(E)-5-((2-methoxyethyl)(methyl)amino)pent-3-en-2-one or(Z)-pent-3-en-2-one,

M¹ is a single bond,

S⁴ is Ar, A or cyclic A which may be mono- or disubstituted with N, —O—or Hal. In preferred embodiments of the present invention 5⁴ is aheteroaromatic 5 to 6 member ring,

M² O, NH, CH₂ or is absent,

S⁵ is H, Ar, A or cyclic A which may be mono- or disubstituted with N,—O—, Hal. In certain embodiments of the present invention S⁵ is selectedfrom the group consisting of but-3-en-2-one, benzene,(E)-5-(dimethylamino)pent-3-en-2-one, ethylbenzene,1-ethyl-2-methoxybenzene, aniline and (E)-5-morpholinopent-3-en-2-one.In some embodiments of the present invention S₅ is absent,

Ar is a mono- or bicyclic aromatic homo- or heterocycle having 0, 1, 2,3 or 4 N, and/or O atoms and 5, 6, 7, 8, 9, or 10 skeleton atoms, whichmay be unsubstituted or, independently of one another, mono-, di- ortrisubstituted by Hal, A, OH, OA, NH₂, NHA, NA₂, NO₂, CN, OCN, COOH,COOA, CONH₂, ONHA, CONA₂, NHCOA, NHCONHA, NHCONH, CHO and/or COA, and inwhich a ring N-atom may be substituted by an O-atom to form an N-oxidegroup and in which in the case of a bicyclic aromatic cycle on of thetwo rings may be partly saturated,

A is unbranched or branched linear or cyclic alkyl having 1, 2, 3, 4, 5,6, 7 or 8 C atoms, in which one or two CH₂ groups may be replaced by anO atom and/or by an —NH—, —CO—, —NHCOO—, —NHCONH—, —N(LA)-, —CONH—,—NHCO— or —CH═CH— group,

LA is unbranched or branched, linear alkyl having 1, 2, 3 or 4 C atoms,wherein 1, 2 or 3 H atoms may be replaced by Hal,

Hal is F, Cl, Br or I.

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of multiple sclerosis (MS), includingrelapsing MS (RMS), relapsing-remitting MS (RRMS), progressive MS (PMS),secondary-progressive MS (SPMS), primary-progressive MS (PPMS), andprogressive-relapsing MS (PRMS), comprising administering to a subject acompound of Formula (IV):

and pharmaceutically acceptable salts, solvates, solvates of salts, orprodrugs thereof, wherein:

Z is N or CH,

X is O or NH, and

R³ is selected from the group consisting of the following structures:

wherein, “R” denotes the bonding point to Z in Formula IV.

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of multiple sclerosis (MS), includingrelapsing MS (RMS), relapsing-remitting MS (RRMS), progressive MS (PMS),secondary-progressive MS (SPMS), primary-progressive MS (PPMS), andprogressive-relapsing MS (PRMS), comprising administering to a subject acompound of Formula (V):

and pharmaceutically acceptable salts, solvates, solvates of salts, orprodrugs thereof,

-   -   in which:    -   X denotes CH or N,    -   R¹ denotes NR⁵[C(R⁵)₂]_(n)Het²,    -   R² denotes Hal, Ar¹ or Het¹,    -   R³ denotes NH₂,    -   R⁴ denotes H, CH₃ or NH₂,    -   R⁵ denotes H or alkyl having 1, 2, 3 or 4 C atoms,    -   R⁶ N(R⁵)₂CH₂CH═CHCONH, Het³CH₂CH═CHCONH, CH₂═CHCONH(CH₂)_(n),        Het⁴(CH₂)_(n)COHet³-diyl-CH₂CH═CHCONH, HC≡CCO, CH₃C≡CCO,        CH₂═CH—CO, CH₂═C(CH₃)CONH, CH₃CH═CHCONH(CH₂)_(n),        N≡CCR⁷R⁸CONH(CH₂)_(n), Het⁴NH(CH₂)_(p)COHet³-diyl-CH₂CH═CHCONH,        Het⁴(CH₂)_(p)CONH(CH₂CH₂O)_(p)(CH₂)_(p)COHet³-diyl-CH₂CH═CHCONH,        CH₂═CHSO₂, ACH═CHCO, CH₃CH═CHCO,        Het⁴(CH₂)_(p)CONH(CH₂)_(p)Het³-diyl-CH₂CH═CHCONH, Ar³CH=CHSO₂,        CH₂═CHSO₂NH or N(R⁵)CH₂CH═CHCO,    -   R⁷, R⁸ denote together alkylene having 2, 3, 4, or 5 C atoms,    -   Ar¹ denotes phenyl or naphthyl, each of which is unsubstituted        or mono-, di- or trisubstituted by R⁶, Hal, (CH₂)_(n)NH₂,        CONHAr³, (CH₂)_(n)NHCOA, O(CH₂)_(n)Ar³, OCyc, A, COHet³, OA        and/or OHet³ (CH₂),    -   Ar² denotes phenyl, naphthyl or pyridyl each of which is        unsubstituted or mono-, di- or trisubstituted by R⁶, Hal, OAr³,        (CH₂)_(n)NH₂, (CH₂)_(n)NHCOA and/or Het³,

Ar³ denotes phenyl, which is unsubstituted or mono-, di- ortrisubstituted by OH, OA, Hal, CN and/or A,

-   -   Het¹ denotes a mono-or bicyclic saturated, unsaturated or        aromatic heterocycle having 1 to 4 N, O and/or S atoms, which        may be unsubstituted or mono-, di- or trisubstituted by R⁶,        O(CH₂)_(n)Ar³ and/or (CH₂)_(n)Ar³,

Het² denotes a mono-or bicyclic saturated heterocycle having 1 to 4 N, Oand/or S atoms, which may be unsubstituted or mono-, di- ortrisubstituted by R⁶, Het³, CycSO₂, OH, Hal, COOH, OA, COA, COHet³,CycCO, SO₂ and/or ═O,

-   -   Het³ denotes a monocyclic unsaturated, saturated or aromatic        heterocycle having 1 to 4 N, O and/or S atoms, which may be        unsubstituted or mono-, di- or trisubstituted by Hal, A and/or        ═O,    -   Het⁴ denotes a bi- or tricyclic unsaturated, saturated or        aromatic heterocycle having 1 to 4 N, O and/or S atoms, which        may be unsubstituted or mono-, di-, tri- or tetrasubstituted by        A, NO₂, Hal and/or ═O,    -   Cyc denotes cyclic alkyl having 3, 4, 5 or 6 C atoms, which is        unsubstituted, monosubstituted or disubstituted by R⁶ and/or OH        and which may comprise a double bond,    -   A denotes unbranched or branched alkyl having 1-10 C atoms, in        which 1-7 H atoms may be replaced by F and/or Cl and/or in which        one or two non-adjacent CH₂ and/or CH-groups may be replaced by        O, NH and/or by N, Hal denotes F, Cl, Br or I,    -   n denotes 0, 1, 2, 3 or 4,    -   p denotes 1, 2, 3, 4, 5 or 6,    -   and pharmaceutically usable salts, tautomers and stereoisomers        thereof, including mixtures thereof in all ratios.

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of multiple sclerosis (MS), includingrelapsing MS (RMS), relapsing-remitting MS (RRMS), progressive MS (PMS),secondary-progressive MS (SPMS), primary-progressive MS (PPMS), andprogressive-relapsing MS (PRMS), comprising administering to a subject acompound selected from Table 2:

TABLE 2 No. Chemical Name “A1”(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one “A2”(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one “A3”N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)phenyl)acrylamide “A4”(R)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-one “A5”N-((1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)acrylamide “A6”1-(4-(((5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)prop-2-en-1-one “A7”N-((1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)piperidin-4-yl)methyl)acrylamide “A8”4-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pipendine-1-carbonyl)-1-methylpyridin- 2(1H)-one “A9”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)but-2-yn-1-one “A10”5-(4-phenoxyphenyl)-N4-((1-(vinylsulfonyl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine “A11”(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-((2-methoxyethyl)(methyl)amino)but-2-en-1-one “A12”(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(2-fluoropyridin-3-yl)methanone “A13”(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)but-2-en-1-one “A14”N4-((1-(cyclopropylsulfonyl)piperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine “A15”(Z)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)but-2-en-1-one “A16”1-(4-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)piperidin-1-yl)prop-2-en-1-one “A17”1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidln-4-yl)oxy)methyl)piperidin-1-yl)prop-2-en-1-one “A18”N-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4- yl)amino)ethyl)acrylamide“A19” (R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one “A20”N-(1-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)cyclopentyl)acrylamide “A21”1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one “A22”1-(4-(((5-fluoro-3-(4-phenoxyphenyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A23”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pipendin-1-yl)ethanone “A24”(E)-7-(3-(4-(4-((3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)amino)-4-oxobut-2-en-1-yl)piperazin-1-yl)-3-oxopropyl)-5,5-difluoro-1,3-dimethyl-5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-5-uide “A25”1-(4-(((2-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A26”(S)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one “A27”N-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4- yl)oxy)ethyl)acrylamide“A28” (S)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-one “A29”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2-methylprop-2-en-1-one “A30”(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(cyclohex-1-en-1-yl)methanone “A31”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-3-methylbut-2-en-1-one “A32”(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(cyclopent-1-en-1-yl)methanone “A33”1-(4-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A34”1-(4-(((6-amino-5-(4-(3-fluorophenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A35”(E)-7-(3-((2-(4-(4-((3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)amino)-4-oxobut-2-en-1-yl)piperazin-1-yl)ethyl)amino)-3-oxopropyl)-5,5-difiuoro-1,3-dimethyl-5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-5-uide “A36”1-(4-(((6-amino-2-methyl-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A37”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)prop-2-en-1-one “A38”(R)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one “A39”1-(4-(((6-amino-5-(4-(phenylamino)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A40”1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-1H-pyrrol-2(5H)-one “A41”1-(4-(((6-amino-5-(4-benzylphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A42”(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(cyclobut-1-en-1-yl)methanone “A43”(Z)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)but-2-en-1-one “A44”1-(4-(((6-amino-2-methyl-5-(4-phenoxyphenyl)pyrimidin-4-yl)(methyl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A45”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2-chloroethanone “A46”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-yn-1-one “A47”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)(methyl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A48”1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one “A49”N-((1S,3S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclopentyl)acrylamide “A50”N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4- yl)amino)butyl)acrylamide“A51” N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide “A52”1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)azepan-1-yl)prop-2-en-1-one “A53”N-(trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide “A54”(E)-5-(4-phenoxyphenyl)-N4-((1-(styrylsulfonyl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine “A55”N4-((1-(methylsulfonyl)piperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine “A56”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2,3-dihydroxypropan-1-one “A57”4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-2-one “A58”N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)ethenesulfonamide “A59”N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)propyl)acrylamide “A60”N-(5-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)pyridin-3-yl)acrylamide “A61”(R)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-yn-1-one “A62”(R,E)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)-4-(dimethylamino)but-2-en-1- one “A63”(E)-N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)-4-(dimethylamino)but-2-enamide “A64”N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)propiolamide “A65”(S)-1-(2-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2-en-1-one “A66”(R)-1-(2-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2-en-1-one “A67”N-(3-((6-amino-5-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A68”1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-yn-1-one “A69”N-(3-((6-amino-5-(1-(4-cyanobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A70”N-(3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)phenyl)acrylamide “A71”(E)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]octan-8-yl)-4-(dimethylamino)but-2-en-1-one “A72”N-(3-((6-amino-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A73”(R,E)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)-4-(dimethylamino)but-2-en-1-one “A74”(R,E)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one “A75”1-(trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-4-hydroxypyrrolidin-1-yl)prop-2-en-1-one “A76”1-(4-(((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A77”1-(4-(((6-amino-5-(4-fluorophenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A78”1-(4-(((6-amino-5-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A79”1-(4-(((6-amino-5-(4-(4- (trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A80”1-(4-(((6-amino-5-(4-(4-(fluorophenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A81”1-(4-(((6-amino-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A82”1-(4-(((6-amino-5-(3,4-dimethoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A83”1-(4-(((6-amino-5-(3,4,5-trimethoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A84”1-(4-(((6-amino-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A85”1-(4-(((6-amino-5-(4-methoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A86”4-(4-(4-(((1-acryloylpiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile “A87”1-(4-(((6-amino-5-(2,5-difluoro-4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A88”1-(4-(((6-amino-5-(2,3-difluoro-4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A89”1-(4-(((6-amino-5-(4-((1-methylpiperidin-4-yl)oxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A90” 1-(4-(((6-amino-5-(4-phenoxy-2-(tnfluoromethyl)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A91”1-(2-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)prop-2-en-1-one “A92”1-(8-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)prop-2-en-1-one “A93”1-(7-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)prop-2-en-1-one “A94”1-(4-(((6-amino-5-(4-(4-hydroxyphenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A95”1-(4-(((6-amino-5-(4-(3- (trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A96”1-(4-(((6-amino-5-(4-(pyridin-3-yloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A97”1-(4-(((6-amino-5-(4-(pyridin-4-yloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A98”1-(4-(((6-amino-5-(4-(p-tolyloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A99”1-(4-(((6-amino-5-(4-(cyclohexyloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A100”N4-((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-ylmethyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine hydrochloride “A101”(3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-3-ol hydrochloride “A102”(E)-1-(6-((6-amino-5-chloropyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-4-(dimethylamino)but-2-en-1-one “A103”1-(3-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)azetidin-1-yl)prop-2-en-1-one “A104”1-(3-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)azetidin-1-yl)prop-2-yn-1-one “A105”(E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-4-(dimethylamino)but-2-en-1-one “A106”1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one “A107”1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one “A108”1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)but-2-yn-1-one “A109”1-((3S,4S)-4-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-en-1-one “A110”1-((3S,4S)-4-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-yn-1-one “A111”1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2-yn-1-one “A112”1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2-yn-1-one “A113”1-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-6-azaspiro[3.4]octan-6-yl)prop-2-en-1-one “A114”1-(6-((6-amino-5-(4-(pyridin-4-yloxy)phenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one “A115”1-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-6-azaspiro[3.4]octan-6-yl)prop-2-yn-1-one “A116”1-(6-((6-amino-5-(1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2-en- 1-one“A117” N-(1,3-trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide “A118”N-((1,3-cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide “A119”N4-(2-((2-chloroethyl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine “A120”1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl) prop-2-en-1-one “A121”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-methoxypipendin-1-yl)prop-2-en-1-one “A122”N-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)spiro[3.3]heptan-2-yl)acrylamide “A123”1-(1-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-7-azaspiro[3.5]nonan-7-yl)prop-2-en-1-one “A124”1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one “A125”1-(8-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-azaspiro[3.5]nonan-5-yl)prop-2-en-1-one “A126”(E)-1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-4-(dimethylamino)but-2-en-1-one “A127”(E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)-4-(dimethylamino)but-2-en-1-one “A128”3-((6-Amino-5-chloro-pyrimidin-4-ylamino)-methyl)- benzoic acid methylester “A129” Trans-3-(6-Amino-5-chloro-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methyl ester “A130”(1R,3S)-3-(6-Amino-5-chloro-pyrimidin-4-ylamino)- cyclohexanecarboxylicacid methyl ester “A131”3-((6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)- methyl)-benzoicacid methyl ester “A132”Trans-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methyl ester “A133”(1R,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methyl ester “A134”-((6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)- methyl)-benzoicacid “A135” (1S,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid “A136”(1R,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid “A137”(4-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-N-methoxy-N-methyl-acetamide “A138”3-((6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-N-methoxy-N-methyl-benzamide “A139”(1S,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methoxy-methyl-amide “A140”(1R,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methoxy-methyl-amide “A141”1-(3-((6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-methyl)-phenyl)-but-2-yn-1-one “A142”1-(3-((6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-methyl)-phenyl)-but-2-en-1-one “A143”1-((1S,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-propenone “A144”1-((1S,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-en-1-one “A145”1-((1S,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-yn-1-one “A146”1-((1S,3R)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-en-1-one “A147”1-((1S,3R)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-yn-1-one “A148”(S)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one “A149”N-(3-((2-amino-3-(4-(benzyloxy)phenyl)pyridin-4-yl)oxy)phenyl)acrylamide “A150”1-(3-((2-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one “A151”(E)-N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide “A152”(E)-N-(3-((2-amino-3-(4-(benzyloxy)phenyl)pyridin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide “A153”(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-(dimethylamino)but-2- en-1-one “A154”N-cis-4-((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide “A155”4-(4-(((1-acryloylpyrrolidin-3-yl)methyl)amino)-6-aminopyrimidin-5-yl)-N-phenylbenzamide “A156”1-(3-(((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-one “A157” 4-(4-(((1-acryloylpiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)-N-phenylbenzamide “A158”N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)-4-fluorophenyl)acrylamide “A159”4-(4-((cis-4-acrylamidocyclohexyl)amino)-6-aminopyrimidin-5-yl)-N-phenylbenzamide “A160”(E)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one “A161”N-(3-((6-amino-5-(6-phenoxypyridin-3-yl)pyrimidin-4-yl)oxy)-4-fluorophenyl)acrylamide “A162”N-(3-((6-amino-5-(4-(pyridin-2-yloxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A163”N-(3-((6-amino-5-(3-sulfamoylphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A164”N-(3-((6-amino-5-(3-(trifluoromethoxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A165”N-(3-((6-amino-5-(6-(2-fluorophenoxy)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A166”N-(3-((6-amino-5-(6-(4-fluorophenoxy)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acryiamide “A167”N-(6-((5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyridin-2- yl)acrylamide“A168” 1-(4-(((6-amino-5-(6-phenoxypyridin-3-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A169”1-(4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)prop-2-en-1-one “A170”1-((3S,4S)-4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-en-1-one “A171”1-(4-(((6-amino-2′-phenoxy-[5,5′-bipyrimidin]-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A172”N-(3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A173”N-((1S,3R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide “A174”N-((1R,3S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide “A175”N-((1R,3R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide “A176”N-((1S,3S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acryiamide “A177”N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)bicyclo[2.1.1]hexan-1-yl)acrylamide “A178”(R)-N4-(1-((perfluorophenyl)sulfonyl)pyrrolidin-3-yl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine “A179”(R)-N4-(1-((perfluorophenyl)sulfonyl)pipendin-3-yl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine “A180”(R)-1-(3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one “A181”N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclopentyl)acrylamide “A182”N-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)cyclobutyl)acrylamide “A183”N-(3-((6-amino-5-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A184”N-(3-((6-amino-5-(1-(2-fluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A185”1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)azetidin-1-yl)prop-2-en-1-one “A186”N-(5-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)acrylamide “A187”N-(3-((6-amino-5-(1-(4-fluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A188”N-((1R,3S,5R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-hydroxycyclohexyl)acrylamide(racemic) “A189”N-(5-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-3-yl)acrylamide “A190”N-(3-((6-amino-5-(1-(3-methylbenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A191”N-(3-((6-amino-5-(1-(3-chlorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A192”(R)-1-(2-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2-en-1-one “A193”(S)-1-(2-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2-en-1-one “A194”N-(3-((6-amino-5-(1-(2-cyanobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A195”N-(3-((6-amino-5-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A196”(R)-1-(3-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one “A197”N-(5-((6-amino-5-(4-(4-cyanophenoxy)phenyl)pyrimidin-4-yl)oxy)pyridin-3-yl)acrylamide “A198”N-(3-((6-amino-5-(1-(3-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acryiamide “A199”4-(4-(4-((((3S,4S)-1-acryloyl-3-hydrpxypiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile “A200”(R)-4-(4-(4-((4-acryloylmorphoiin-2-yl)methoxy)-6-aminopyrimidin-5-yl)phenoxy)benzonitriie “A201”(R)-4-(4-(4-((1-acryloylpyrrolidin-3-yl)methoxy)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile “A202”4-(4-(4-((2-acryloyl-2-azaspiro[3.3]heptan-6-yl)oxy)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile “A203”N-(3-((6-amino-5-(1-(3-cyanobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A204”1-((3S,5S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-fluoropiperidin-1-yl)prop-2-en-1-one “A205”1-((3R,5R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-fluoropiperidin-1-yl)prop-2-en-1-one “A206” methyl3-((4-(4-(3-acrylamidophenoxy)-6-aminopyrimidin-5-yl)-1H-pyrazol-1-yl)methyl)benzoate “A207”4-(4-(4-((2-acryloyl-2-azaspiro[3.3]heptan-6-yl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile “A208”4-(4-(4-(((8-acryloyl-8-azabicyclo[3.2.1]octan-3-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile “A209”1-(3-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one “A210”1-((3R,4R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-4-hydroxypiperidin-1-yl)prop-2-en-1-one(racemic) “A211”N-(3-((6-amino-5-(1-(3-(methylsulfonyl)benzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A212”N-(3-((6-amino-5-(1-(3-(dimethylamino)benzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A213”N-(3-((6-amino-5-(4-(3-cyanophenoxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A214”3-(4-(4-(((1-acryloylpiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile “A215”1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)but-2-yn-1-one “A216”1-acryloyl-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidine-4-carboxylic acid “A217”(E)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-1-(4-(dimethylamino)but-2-enoyl)piperidine-4-carboxylic acid “A218”(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-(3-fluoroazetidin-1-yl)but-2- en-1-one“A219” (E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-(3,3-difluoroazetidin-1-yl)but-2-en-1-one “A220” (E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-(pyrrolidin-1-yl)but-2-en- 1-one“A221” 1-(6-((6-amino-5-(4-(pyridin-3-yloxy)phenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one “A222”(E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-4-(3-fluoroazetidin-1-yl)but-2-en- 1-one“A223” (E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-4-(3-fluoroazetidin-1-yl)but-2-en- 1-one“A224” (E)-N-(1,3-cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)-4-(dimethylamino)but-2-enamide “A225”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropipendin-1-yl)prop-2-en-1-one; compound(2)“A226” (E)-1-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-6-azaspiro[3.4]octan-6-yl)-4-(dimethylamino)but-2-en-1-one “A227”(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)-4-(dimethylamino)but-2-en-1-one “A228”(E)-N-(1,3-trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)-4-(dimethylamino)but-2-enamide “A229”N-(1,3-cis-3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide “A230”(E)-N-(1,3-cis-3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclobutyl)-4-(dimethylamino)but- 2-enamide“A231” (E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-3-phenylprop-2-en-1-one “A232”1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3- (dimethylamino)propan-1-one“A233” 1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypipendln-1-yl)-3-(piperidin-1- yl)propan-1-one“A234” 1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-morpholinopropan- 1-one“A235” 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)-3-(piperidin-1- yl)propan-1-one“A236” (E)-N-(1,3-cis-3-((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)cyclobutyl)-4-(dimethylamino)but-2-enamide “A237”N-(1,3-trans-3-((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide “A238” N-(1,3-cis-3-((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide “A239” 1-acryloyl-4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidine-4-carboxylic acid “A240”N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-fluoropheny)acrylamide “A241”N-(3-(4-amino-6-((4-phenoxyphenyl)amino)pyrimidin-5-yl)phenyl)acrylamide “A242”N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4- yl)oxy)phenyl)acrylamide“A243” N-(3-(2-amino-4-(4-phenoxyphenoxy)pyridin-3- yl)phenyl)acrylamide“A244” N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide “A245”N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5- yl)phenyl)acrylamide“A246” N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-4-fluorophenyl)acrylamide “A247”(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one “A248”(E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-(dimethylamino)but-2-enamide “A249”N-(3-((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A250”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one; compound (1) “A251”N-(5-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2,4-difluorophenyl)acrylamide “A252”(E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide “A253”1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one “A254”N-(3-((6-amino-5-(4-((2-methoxybenzyl)oxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A255” N-(3-((5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A256”N-(3-((6-amino-5-(4-(benzyloxy)-3-methoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A257”N-(3-((6-amino-5-(4-(benzyloxy)-2,3-difluorophenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A258”4-(4-(3-acrylamidophenoxy)-6-aminopyrimidin-5-yl)-N- phenylbenzamide“A259” N-(3-((6-amino-5-(6-(benzyloxy)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A260”N-(3-((6-amino-5-(4-((3-fluorobenzyl)oxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A261”N-(3-((6-amino-2′-(benzyloxy)-[5,5′-bipyrimidin]-4-yl)oxy)phenyl)acrylamide “A262”1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-one “A263”1-(4-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one “A264”N-(3-((6-amino-5-(4-((4-methoxybenzyl)oxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A265”(E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-morpholinobut-2-enamide “A266”N-((1s,4s)-4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide “A267”N-(3-(4-((4-phenoxyphenyl)amino)pyridin-3- yl)phenyl)acrylamide “A268”N-(3-((6-amino-5-(6-phenoxypyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A269”1-(3-((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one “A270”N-(3-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide “A271”N-(3-((2-amino-5-(4-phenoxyphenyl)pyrimidin-4- yl)oxy)phenyl)acrylamide“A272” 3-(3-acrylamidophenyl)-4-(4-phenoxyphenoxy)picolinamide “A273”1-(3-(4-amino-6-((4-phenoxyphenyl)amino)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one “A274”(E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-morpholinobut-2-enamide “A275”(S)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one “A276”N-((1r,4r)-4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide “A277”N-(3-((6-amino-5-(4-fluoro-3-methoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A278”N-(3-((6-amino-5-(4-(2-hydroxypropan-2-yl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A279”1-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one “A280”N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4- yl)oxy)phenyl)acrylamide“A281” N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)acrylamide “A282”(E)-4-(dimethylamino)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide “A283”N-(3-(4-((4-phenoxyphenyl)amino)pyrimidin-5- yl)phenyl)acrylamide “A284”1-(3-((5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one “A285”N-(3-((6-amino-5-(4-(pyrrolidine-1-carbonyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A286”1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A287”N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)acrylamide “A288”1-(4′-(4-phenoxyphenoxy)-5,6-dihydro-[3,3′-bipyridin]-1(2H)-yl)prop-2-en-1-one “A289”N-(3-((6-amino-5-(4-isopropoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A290”(E)-N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide “A291”N-(3-((6-amino-5-(5-methoxypyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A292”1-(4-(((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A293”(E)-4-morpholino-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide “A294”N-(3-((6-amino-5-(4-(benzyloxy)-2,6-difluorophenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A295”(E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(4-(5-((4S)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl)piperazin-1-yl)but-2-enamide “A296”N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-ynamide “A297”N-(4-((3-(4-phenoxyphenyl)pyndin-4-yl)oxy)phenyl)acrylamide “A298”N-(1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)piperidin-3-yl)acrylamide “A299” 1-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one “A300”3-(3-aminophenyl)-4-(4-phenoxyphenoxy)pyridin-2-amine “A301”(E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-(3,3-difluoropiperidin-1-yl)but-2-enamide “A302”N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)acrylamide “A303”6-(4-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine “A304”N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)but-2-ynamide “A305”6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine “A306”N-(3-(2-amino-4-(4-phenoxyphenoxy)pyrimidin-5- yl)phenyl)acrylamide“A307” (E)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2- enamide“A308” N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)propionamide “A309”N-((1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)pipendin-3-yl)methyl)acrylamide “A310” N-(3-(2-amino-4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide “A311”(R)-N-(3-(4-amino-6-((1-phenylethyl)amino)pyrimidin-5-yl)phenyl)acrylamide “A312” 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline“A313” 4-(3-aminophenoxy)-3-(4-phenoxyphenyl)pyridin-2-amine “A314”4-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline “A315”(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine “A316”(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine “A317”5-(3-aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amine “A318”N-(3-((3-(4-phenoxyphenyl)pyridin-4- yl)oxy)phenyl)propionamide “A319”N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide “A320”N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide “A321”N-(4-((3-(4-phenoxyphenyl)pyridin-4- yl)oxy)phenyl)propionamide “A322”N-(3-(4-(4-phenoxyphenoxy)pyridin-3- yl)phenyl)methacrylamide “A323”N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)propionamide “A324”N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)propionamide “A325”N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5- yl)phenyl)propionamide“A326” N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)propionamide “A327”(E)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)but-2- enamide “A328”3-(4-phenoxyphenyl)-4-(3-propionamidophenoxy)picolinamide “A329”N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-1-cyanocyclopropanecarboxamide “A330”N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-1-cyanocyclopropanecarboxamide “A331”(E)-3-(7-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)naphthalen-2-yl)-N,N-dimethylacrylamide “A332”1-(4-(1-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)piperidin-1-yl)prop-2-en-1-one “A333”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)propan-1-one “A334”1-(4-(((5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A335”1-(4-(((6-amino-5-(4-(pyridin-2-yloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A336”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)but-2-yn-1-one “A337”N4-((1-(6-chloropyridin-2-yl)piperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine “A338”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)prop-2-en-1-one “A339”N-(3-((6-amino-5-(4-(benzyloxy)-2,5-difluorophenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A340”N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4- yl)oxy)phenyl)but-2-ynamide“A341” (R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)but-2-yn-1-one “A342”N-{3-[6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-yloxy]-phenyl}-2-chloroacetamide “A343”N-(3-{6-Amino-5-[4-(2-fluoro-benzyloxy)-phenyl]-pyrimidin-4-yloxy}-phenyl)-acrylamide “A344”N-(3-{6-Amino-5-[4-(4-fluoro-benzyloxy)-phenyl]-pyrimidin-4-yloxy}-phenyl)-acrylamide “A345”N-(3-{6-Amino-5-[4-(3-fluoro-benzyloxy)-phenyl]-pyrimidin-4-yloxy}-phenyl)-2-chloro-acetamide “A346”N-{3-[6-Amino-5-(4-benzyloxy-phenyl)-pyrimidin-4-yloxy]-phenyl}-propionamide “A347”N-{3-[6-Amino-5-(4-benzyloxy-phenyl)-pyrimidin-4-yloxy]-phenyl}-2-chloro-acetamide “A348”N-{3-[6-Amino-5-(4-benzyloxy-3-fluoro-phenyl)-pyrimidin-4-yloxy]-phenyl}-acrylamide “A349”N-{3-[6-Amino-5-(4-benzyloxy-2-fluoro-phenyl)-pyrimidin-4-yloxy]-phenyl}-acrylamide “A350”N-{3-(6-Amino-5-(4-benzyloxy-2-fluoro-phenyl)-pyrimidin-4- yloxy} -phenyl)-2-chloro-acetamide “A351”N-{3-[6-Amino-5-(4-benzyloxy-3-fluoro-phenyl)-pyrimidin-4-yloxy]-phenyl}-2-chloro-acetamide “A352”N-{4-[4-(3-Acryloylamino-phenoxy)-6-amino-pyrimidin-5-yl]-phenyl}-benzamide

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of multiple sclerosis (MS), includingrelapsing MS (RMS), relapsing-remitting MS (RRMS), progressive MS (PMS),secondary-progressive MS (SPMS), primary-progressive MS (PPMS), andprogressive-relapsing MS (PRMS), comprising administering to a subject acompound selected from:

N-[(1-acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine(1); and1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one(2).

In certain embodiments, the invention provides a method as describedabove, wherein the compound isN-[(1-acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyOpyrimidine-4,6-diamine(1).

In certain embodiments, the invention provides a method as describedabove, wherein the compound is1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one(2).

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of multiple sclerosis (MS), comprisingadministering to a subject, compound (1).

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of multiple sclerosis (MS), comprisingadministering to a subject, compound (2).

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of relapsing MS (RMS), comprisingadministering to a subject, compound (1).

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of relapsing MS (RMS), comprisingadministering to a subject, compound (2).

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of relapsing-remitting MS (RRMS),comprising administering to a subject, compound (1).

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of relapsing-remitting MS (RRMS),comprising administering to a subject, compound (2).

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of progressive MS (PMS), comprisingadministering to a subject, compound (1).

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of progressive MS (PMS), comprisingadministering to a subject, compound (2).

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of secondary-progressive MS (SPMS),comprising administering to a subject, compound (1).

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of secondary-progressive MS (SPMS),comprising administering to a subject, compound (2).

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of primary-progressive MS (PPMS),comprising administering to a subject, compound (1).

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of primary-progressive MS (PPMS),comprising administering to a subject, compound (2).

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of progressive-relapsing MS (PRMS),comprising administering to a subject, compound (1).

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of progressive-relapsing MS (PRMS),comprising administering to a subject, compound (2).

In general, all residues which occur more than once may be identical ordifferent, i.e. are independent of one another. Above and below, theresidues and parameters have the meanings indicated for Formula (I),Formula (II), Formula (III), Formula (IV) and Formula (V) unlessexpressly indicated otherwise. Accordingly, the invention relates, inparticular, to the compounds of Formula (I), Formula (II), Formula(III), Formula (IV) and Formula (V) in which at least one of the saidresidues has one of the preferred meanings indicated below.

The term “substituted” preferably relates to the substitution by theabove-mentioned substituents, where a plurality of different degrees ofsubstitution are possible, unless indicated otherwise.

All physiologically acceptable salts, derivatives, solvates, solvates ofsalts, and stereoisomers of these compounds, including mixtures thereofin all ratios, are also in accordance with the invention.

The compounds of the Formula (I), (II), (III), (IV) and (V) may have oneor more centres of chirality. They may accordingly occur in variousenantiomeric forms and be in racemic or optically active form. Theinvention therefore also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andhydrates and solvates of these compounds.

Since the pharmaceutical activity of the racemates or stereoisomers ofthe compounds according to the invention may differ, it may be desirableto use the enantiomers. In these cases, the end product or even theintermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or evenemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids, such as the R andS forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid, suitably N-protected amino acids(for example N-benzoylproline or N-benzenesulfonylproline), or thevarious optically active camphorsulfonic acids. Also advantageous ischromatographic enantiomer resolution with the aid of an opticallyactive resolving agent (for example dinitrobenzoylphenylglycine,cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel). Suitableeluents for this purpose are aqueous or alcoholic solvent mixtures, suchas, for example, hexane/isopropanol/ acetonitrile, for example in theratio 82:15:3. An elegant method for the resolution of racematescontaining ester groups (for example acetyl esters) is the use ofenzymes, in particular esterases.

It is also contemplated that compounds of Formula (I), Formula (II),Formula (III), Formula (IV) and Formula (V) include isotope-labeledforms thereof. An isotope-labeled form of a compound of Formula (I),Formula (II), Formula (III), Formula (IV) and Formula (V) is identicalto this compound apart from the fact that one or more atoms of thecompound have been replaced by an atom or atoms having an atomic mass ormass number which differs from the atomic mass or mass number of theatom which usually occurs naturally. Examples of isotopes which arereadily commercially available and which can be incorporated into acompound of the Formula I by well-known methods include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine,for example ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and³⁶CI, respectively. It is also contemplated that a compound of theFormula I, a prodrug, thereof or a pharmaceutically acceptable salt ofeither which contains one or more of the above-mentioned isotopes and/orother iso-topes of other atoms are embodiments of the present invention.An isotope-labeled compound of the Formula I can be used in a number ofbeneficial ways. For example, an isotope-labeled compound of the FormulaI into which, for example, a radioisotope, such as ³H or ¹⁴C, has beenincorporated, is suitable for medicament and/or substrate tissuedistribution assays. These radioisotopes, i.e. tritium (³H) andcarbon-14 (¹⁴C), are particularly preferred owing to their ease ofpreparation and excellent detectability. Incorporation of heavierisotopes, for example deuterium (²H), into a compound of the Formula Imay have therapeutic advantages owing to the higher metabolic stabilityof this isotope-labeled compound. Higher metabolic stability translatesdirectly into an increased in vivo half-life or lower dosages, whichunder some circumstances would represent a preferred embodiment of thepresent invention. An isotope-labeled compound of the Formula I can beadapted to the procedures disclosed in the synthesis schemes and therelated description, in the example part and in the preparation part inthe present text, replacing a non-isotope-labeled reactant by a readilyavailable isotope-labeled reactant.

In other embodiments it is contemplated that deuterium (²H) may beincorporated into a compound of Formula (I), Formula (II), Formula(III), Formula (IV) and Formula (V). Such deuterated compounds canmodify the oxidative metabolism of said deuterated compound by means theprimary kinetic isotope effect. The primary kinetic isotope effect is achange of the rate for a chemical reaction that results from exchange ofisotopic nuclei, which in turn is caused by the change in ground stateenergies necessary for covalent bond formation after this isotopicexchange. Exchange of a heavier isotope usually results in a lowering ofthe ground state energy for a chemical bond and thus causes a reductionin the rate in rate-limiting bond breakage. If the bond breakage occursin or in the vicinity of a saddle-point region along the coordinate of amulti-product reaction, the product distribution ratios can be alteredsubstantially. For explanation: if deuterium is bonded to a carbon atomat a non-exchangeable position, rate differences of k_(M)/k_(D)=2-7 aretypical. If this rate difference is observed in any compounds of Formula(I), Formula (II), Formula (III), Formula (IV) and Formula (V)susceptible to oxidation, the profile of this compound, in vivo, can bedrastically modified and result in improved pharmacokinetic properties.

When discovering and developing therapeutic agents, the person skilledin the art attempts to optimize pharmacokinetic parameters whileretaining desirable in vitro properties. It is reasonable to assume thatmany compounds with poor pharmacokinetic profiles are susceptible tooxidative metabolism. In vitro liver microsomal assays known in the artmay provide valuable information on the course of oxidative metabolismof this type, which in turn permits the rational design of deuteratedcompounds of Formula (I), Formula (II), Formula (III), Formula (IV) andFormula (V) with improved stability through resistance to said oxidativemetabolism. Significant improvements in the pharmacokinetic profiles ofcompounds of the Formula I may thereby be obtained, and can be expressedquantitatively in terms of increases in the in vivo half-life (t/2),concentration at maximum therapeutic effect (C_(max)), area under thedose response curve (AUC), and F; and in terms of reduced clearance,dose and materials costs.

While it is not intended that the present invention be limited to anydeuterated motif, the following is an example. A compound of Formula(I), Formula (II), Formula (III), Formula (IV) and Formula (V) which hasmultiple potential sites of attack for oxidative metabolism, for examplebenzylic hydrogen atoms and hydrogen atoms bonded to a nitrogen atom, isprepared as a series of analogues in which various combinations ofhydrogen atoms are replaced by deuterium atoms, so that some, most orall of these hydrogen atoms have been replaced by deuterium atoms.Half-life determinations enable favorable and accurate determination ofthe extent of the extent to which the improve-ment in resistance tooxidative metabolism has improved. In this way, it can be determinedthat the half-life of the parent compound may be extended by up to 100%as the result of deuterium-hydrogen exchange of this type.

Deuterium-hydrogen exchange in a compound of Formula (I), Formula (II),Formula (III), Formula (IV) and Formula (V) can also be used to achievea favorable modification of the metabolite spectrum of the startingcompound in order to diminish or eliminate undesired toxic metabolites.For example, if a toxic metabolite arises through oxidativecarbon-hydrogen (C—H) bond cleavage, it can reasonably be assumed thatthe deuterated analogue will greatly diminish or eliminate production ofthe unwanted metabolite, even if the particular oxidation is not arate-determining step. Further information on the state of the art withrespect to deuterium-hydrogen exchange may be found, for example inHanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J.Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985,Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al.Carcinogenesis 16(4), 683-688, 1993.

The compounds of the present invention can be in the form of a prodrugcompound. “Prodrug compound” means a derivative that is converted into abiologically active compound according to the present invention underphysiological conditions in the living body, e.g., by oxidation,reduction, hydrolysis or the like, each of which is carried outenzymatically, or without enzyme involvement. Examples of prodrugs arecompounds, wherein the amino group in a compound of the presentinvention is acylated, alkylated or phosphorylated, e.g.,eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein thehydroxyl group is acylated, alkylated, phosphorylated or converted intothe borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy,fumaryloxy, alanyloxy or wherein the carboxyl group is esterified oramidated, or wherein a sulfhydryl group forms a disulfide bridge with acarrier molecule, e.g. a peptide, that delivers the drug selectively toa target and/or to the cytosol of a cell. These compounds can beproduced from compounds of the present invention according to well-knownmethods. Other examples of prodrugs are compounds, wherein thecarboxylate in a compound of the present invention is for exampleconverted into an alkyl-, aryl-, choline-, amino, acyloxymethylester,linolenoyl-ester.

Metabolites of compounds of the present invention are also within thescope of the present invention.

Where tautomerism, e.g., keto-enol tautomerism, of compounds of thepresent invention or their prodrugs may occur, the individual forms,e.g., the keto or the enol form, are claimed separately and together asmixtures in any ratio. The same applies for stereoisomers, e.g.,enantiomers, cis/trans isomers, conformers and the like.

If desired, isomers can be separated by methods well known in the art,e.g. by liquid chromatography. The same applies for enantiomers, e.g.,by using chiral stationary phases. Additionally, enantiomers may beisolated by converting them into diastereomers, i.e., coupling with anenantiomerically pure auxiliary compound, subsequent separation of theresulting diastereomers and cleavage of the auxiliary residue.Alternatively, any enantiomer of a compound of the present invention maybe obtained from stereoselective synthesis using optically pure startingmaterials

The compounds of the present invention can be in the form of apharmaceutically acceptable salt or a solvate. The term“pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic bases or acids, includinginorganic bases or acids and organic bases or acids. In cases where thecompounds of the present invention contain one or more acidic or basicgroups, the invention also comprises their correspondingpharmaceutically or toxicologically acceptable salts, in particulartheir pharmaceutically utilizable salts. Thus, the compounds of thepresent invention which contain acidic groups can be present in saltform, and can be used according to the invention, for example, as alkalimetal salts, alkaline earth metal salts or as ammonium salts. Moreprecise examples of such salts include sodium salts, potassium salts,calcium salts, magnesium salts or salts with ammonia or organic aminessuch as, for example, ethylamine, ethanolamine, triethanolamine or aminoacids. Compounds of the present invention which contain one or morebasic groups, i.e. groups which can be protonated, can be present insalt form, and can be used according to the invention in the form oftheir addition salts with inorganic or organic acids. Examples ofsuitable acids include hydrogen chloride, hydrogen bromide, phosphoricacid, sulfuric acid, nitric acid, methanesulfonic acid,p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, aceticacid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formicacid, propionic acid, pivalic acid, diethylacetic acid, malonic acid,succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid,sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid,isonicotinic acid, citric acid, adipic acid, and other acids known tothe person skilled in the art. If the compounds of the present inventionsimultaneously contain acidic and basic groups in the molecule, theinvention also includes, in addition to the salt forms mentioned, innersalts or betaines (zwitterions). The respective salts can be obtained bycustomary methods which are known to a person skilled in the art, forexample by contacting these with an organic or inorganic acid or base ina solvent or dispersant, or by anion exchange or cation exchange withother salts. The present invention also includes all salts of thecompounds of the present invention which, owing to low physiologicalcompatibility, are not directly suitable for use in pharmaceuticals butwhich can be used, for example, as intermediates for chemical reactionsor for the preparation of pharmaceutically acceptable salts.

Furthermore, the present invention relates to pharmaceuticalcompositions comprising a compound of the present invention, or aprodrug compound thereof, or a pharmaceutically acceptable salt orsolvate thereof as an active ingredient together with a pharmaceuticallyacceptable carrier.

“Pharmaceutical composition” means one or more active ingredients, andone or more inert ingredients that make up the carrier, as well as anyproduct which results, directly or indirectly, from combination,complexation or aggregation of any two or more of the ingredients, orfrom dissociation of one or more of the ingredients, or from other typesof reactions or interactions of one or more of the ingredients.Accordingly, the pharmaceutical compositions of the present inventionencompass any composition made by admixing a compound of the presentinvention and a pharmaceutically acceptable carrier.

A pharmaceutical composition of the present invention may additionallycomprise one or more other compounds as active ingredients, such as oneor more additional compounds of the present invention, or a prodrugcompound or other BTK inhibitors.

The pharmaceutical compositions include compositions suitable for oral,rectal, topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (nasal or buccalinhalation), or nasal administration, although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient.They may be conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

In one embodiment, said compounds and pharmaceutical composition, orpharmaceutically acceptable salt, prodrug or hydrate thereof, and apharmaceutically acceptable carrier, are for the treatment of multiplesclerosis (MS), including relapsing MS (RMS), relapsing-remitting MS(RRMS), progressive MS (PMS), secondary-progressive MS (SPMS),primary-progressive MS (PPMS), and progressive-relapsing MS (PRMS).

The invention also relates to the use of compounds according to theinvention for the preparation of a medicament for the treatment ofmultiple sclerosis (MS), including relapsing MS (RMS),relapsing-remitting MS (RRMS), progressive MS (PMS),secondary-progressive MS (SPMS), primary-progressive MS (PPMS), andprogressive-relapsing MS (PRMS).

In practical use, the compounds of the present invention can be combinedas the active ingredient in intimate admixture with a pharmaceuticalcarrier according to conventional pharmaceutical compounding techniques.The carrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like. In the case of oral liquidpreparations, any of the usual pharmaceutical media may be employed,such as, for example, suspensions, elixirs and solutions; or carrierssuch as starches, sugars, microcrystalline cellulose, diluents,granulating agents, lubricants, binders, disintegrating agents and thelike. In the case of oral solid preparations the composition may takeforms such as, for example, powders, hard and soft capsules and tablets,with the solid oral preparations being preferred over the liquidpreparations.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form in which case solidpharmaceutical carriers are obviously employed. If desired, tablets maybe coated by standard aqueous or nonaqueous techniques. Suchcompositions and preparations should contain at least 0.1 percent ofactive compound. The percentage of active compound in these compositionsmay, of course, be varied and may conveniently be between about 2percent to about 60 percent of the weight of the unit. The amount ofactive compound in such therapeutically useful compositions is such thatan effective dosage will be obtained. The active compounds can also beadministered intranasally as, for example, liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a bindersuch as gum tragacanth, acacia, corn starch or gelatin; excipients suchas dicalcium phosphate; a disintegrating agent such as corn starch,potato starch, alginic acid; a lubricant such as magnesium stearate; anda sweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Compounds of the present invention may also be administeredparenterally. Solutions or suspensions of these active compounds can beprepared in water suitably mixed with a surfactant such ashydroxy-propylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols and mixtures thereof in oils. Under ordinaryconditions of storage and use, these preparations contain a preservativeto prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dose of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like. Preferably compounds of thepresent invention are administered orally.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration, thecondition being treated and the severity of the condition being treated.Such dosage may be ascertained readily by a person skilled in the art.

The invention also relates to a set (kit) consisting of separate packsof

a) an effective amount of a compound according to the invention or aphysiologically acceptable salt, solvate or prodrug thereof, and

b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules.

The set may, for example, comprise separate ampoules, each containing aneffective amount of a compound according to the invention and/orpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios, and an effective amount of afurther medicament active ingredient in dissolved or lyophilised form.

EXAMPLES

Efficacy of (1) in PLP139-151 Induced EAE in SJL Mice (RelapsingRemitting Mouse Model of MS)

Compound (1) was administered prophylactically in PLP139-151 induced EAEin female SJL mice. Treatment started on Day 0 post-induction: Vehicle,0.3 mg/kg, 1.0 mg/kg, and 3 mg/kg, and FTY-720 at 3 mg/kg. We alsodetermined PK/PD (receptor occupancy) at first dose and at the end ofthe study. The results are provided in FIGS. 1 and 2.

Animals: 75 Female SJL mice from Jax (10 weeks at arrival), at least 18g upon arrival.

Treatment Groups:

Group Treatment Dose Regimen Route N A SHAM n/a n/a n/a 5 B Vehicle n/aProphylactic, QD PO 15 C 1 0.3 mpk Prophylactic, QD PO 15 D 1 1 mpkProphylactic, QD PO 15 E 1 3 mpk Prophylactic, QD PO 15 F FTY-720 3 mpkProphylactic, QD PO 10

Solutions Preparation:

CFA Preparation: Total Volume needed: 10 mL; 2 mg/mL of M.T. was addedto IFA to get a total concentration of 2 mg/mL M.T. in CFA (Add 100 mgM.T. to 50 mL of IFA).

PLP139-151 Preparation: 100 ug PLP₁₃₉₋₁₅₁: Concentration: 1 mg/mL; 25 mgof PLP in 25 mL PBS. Emulsified PLP/CFA in a 1:1 ratio using homogenizermethod.

PTX Preparation: Stock Solution: 1 mL of PBS was added to the vial with50 ug (store in fridge); 60 ng/mouse (0.2 mL/mouse)=0.3 ug/ml (dilutestock 1:167, 210 ul in 35 mL PBS).

Efficacy of (1) in PLP139-151 Induced EAE in SJL Mice (BTKi in aRelapsing Remitting Mouse Model of MS—Therapeutic Dosing)

Compound (1) was administered in PLP139-151 induced EAE in female SJLmice in both prophylactic (treatment start at induction) and therapeutic(treatment start at remission) dosing regimen. The study was adose-response: 0.3, 1 and 3 mg/kg for prophylactic dosing regimen and 1,3 and 10 mg/kg for therapeutic dosing. In addition we determined PK/PDafter 1^(st) and last dose to enable modeling of efficacy vs receptoroccupancy. See FIGS. 3-5.

Animals: 145 Female SJL mice from Jax (10 weeks at arrival), at least 18g upon arrival.

Treatment Groups:

Group Treatment Dose Regimen Route N A SHAM n/a n/a n/a 5 B Vehicle n/aProphylactic, QD PO 15 C (1) 0.3 mpk Prophylactic, QD PO 15 D (1) 1 mpkProphylactic, QD PO 15 E (1) 3 mpk Prophylactic, QD PO 15 F FTY-720 1mpk Prophylactic, QD PO 10 G Vehicle n/a Therapeutic, QD PO 15 H (1) 1mpk Therapeutic, QD PO 15 I (1) 3 mpk Therapeutic, QD PO 15 J (1) 10 mpkTherapeutic, QD PO 15 K FTY-720 1 mpk Therapeutic, QD PO 10

Induction of EAE in SJL Mice:

PLP₁₃₉₋₁₅ was dissolved in PBS and emulsified with an equal volume ofCFA supplemented with 2 mg/mL mycobacterium tuberculosis (M.T.) (CFAalready has 1 mg/ml MT so another 1 mg/ml is added to a finalconcentration of 2 mg/ml). Mice were injected s.c. with 0.2 ml ofpeptide emulsion in the abdominal flank (0.1 ml on each side). On thesame day and 48 hr later, mice were injected i.p. with 200 μl (60 ng) ofBordetella Pertussis toxin in saline.

Solutions Preparation:

CFA Preparation: Total Volume needed: 10 mL; Add 2 mg/mL of M.T. to IFAto get a total concentration of 2 mg/mL M.T. in CFA (add 100 mg M.T. to50 mL of IFA).

PLP139-151 Preparation: 100 ug PLP₁₃₉₋₁₅₁: Concentration: 1 mg/mL; 25 mgof PLP in 25 mL PBS; PLP/CFA was emulsified in a 1:1 ratio usinghomogenizer method.

PTX Preparation: Stock Solution: Add 1 mL of PBS to the vial with 50 ug(store in fridge); 60 ng/mouse (0.2 mL/mouse)=0.3 ug/ml (dilute stock1:167, 210 ul in 35 mL PBS).

BTK Occupancy in Mouse Blood (Compounds 1 and 2)

To calculate the amount of Btk occupancy achieved after dosing with aBtk inhibitor samples were collected from vehicle treated mice. Thevehicle group samples were assumed to have 0% occupancy and % occupancyfor the Btk inhibitor treated mice was calculated relative to this 0%value. Blood was collected and dispensed into anti-coagulant coatedtubes. Either EDTA or heparin were acceptable anti-coagulants. Thecollected blood was kept at room temperature (20-24 C) until processing.Blood (80 μl) was transferred to a 1.5 ml eppendorf snap cap tube usinga pipet. 800 μl of room temperature red blood cell lysis buffer wasadded, the tube capped, and inverted 3 times to mix. The mixture wasincubated for 5 minutes at room temperature. The cells were pelletted bycentrifugation for 5 minutes at 600×g at room temperature and thenaspirated without disturbing the cell pellet. The cells were washed byresuspending in 400 μl of RBC lysis buffer using a pipet followed bycentrifugation for 5 minutes at 600×g (room temperature) and carefulaspiration of the liquid. A stock of incubation media was made bycombining RPMI1640 and the Btk occupancy probe compound. Media waswithout any added FBS or Pen/Strep. The probe compound was previouslydissolved in DMSO to 10 mM and stored in aliquots at −80 C. 1 μl of 10mM probe compound per 10 ml of RPMI1640 was added to make the incubationmedia stock containing a final of 1 μM probe. The pelletted cells wereresuspend with 1 ml of incubation media containing the probe. The cellswere incubated with the probe for 1 hr at 37 C in a CO₂ regulated tissueculture incubator with the tube lids open. The lysis buffer was preparedduring the 1 hr incubation (Add 10 μl of HALT protease and phosphataseinhibitor cocktail per ml of MPER lysis buffer. Chill mixed buffer onice at least 10 minutes before use). After 1 hr incubation, the cellswere pelletted by centrifugation at room temperature for 5 minutes at600×g. The media was aspirated and cells were resuspended in 120 μl ofchilled MPER lysis buffer. Incubate on ice after addition of lysisbuffer and subsequently store samples at −80 C before usage in the MSDoccupancy assay.

The probe:

Probe-treated cell lysates were thawed and biotinylated-Btk wasquantitated using a streptavidin capture assay performed on the MSDplatform. MSD microtiter plates coated with streptavidin were blocked byincubation with 200 μl/well of casein-containing blocking buffer fromPierce for 1 hr. This incubation and all other incubations in the assaywere performed at room temperature with gentle shaking at 200 rpm on amicrotiter plate shaker and the plate was covered using a plasticadhesive sealer film. After blocking, the plates were washed 1×200μl/well (PBS/0.05% tween 20). Add 100 μl/well of standards. The celllysates were dilued (10 μl+200 μl) of blocking buffer in a separatedilution plate prior to addition. 50 μl of diluted cell lysate was addedto 50 μl of blocking buffer per well to a final volume of 100 μl/well.It was allowed to incubate for 1.5-2 hr at room temperature. Thestandards were assayed in duplicate as well as unknown samples. Theplate was washed (3×200 μl/well (PBS/0.05% tween 20)) and rabbitanti-Btk antibody was added (100 μl/well) diluted to 1 μg/ml (1:1,000)in blocking buffer. The solution was incubated for 1.5-2 hr at room tempwith shaking. The plate was washed (3×200 μl/well (PBS/0.05% tween 20))and goat anti-rabbit SULFO-tagged antibody was added (100 μl/well)diluted to 1 μg/ml (1:500) in blocking buffer. The solution wasincubated for 1.5-2 hr at room temp with shaking. The plate was washed(3×200 μl/well) (PBS/0.05% tween 20), then diluted (4×MSD Read Buffer)to a 2× concentration with water and then added 150 μl/well. The platewas immediately read using an MSD Sector Imager 600. The data wasprocessed using the MSD Discovery Workbench software program.

A standard curve employing recombinant Btk previously treated withbiotinylated probe in vitro was used for quantitation. To generate thestock standard, recombinant Btk was treated in vitro at 2 ng/μl in PBScontaining 1 mg/ml BSA with 1 μM of the probe for 1 hr at 37 C and thenfrozen in aliquots at −80 C.

To generate the standard curve an aliquot of the stock of therecombinant Btk standard was diluted 5 μl+245 μl of blocking buffer. Thediluted standard was then further diluted in blocking buffer with serial1:2 dilutions (70 μl+140 μl of blocking buffer). The standards wereprepared in the 96 dilution plate same as the samples. The standardcurve values for Btk-biotin range from 40 to 0.02 ng/ml. Curve fittingwas performed with a four parameter fit in the MSD Discovery Workbenchsoftware program.

The assay described above measures probe binding to Btk where inhibitorshave not covalently attached to the active site and therefore detectsunoccupied Btk. Thus, samples collected from vehicle treated micecontain cells with totally unoccupied Btk and the amount of Btk-biotindetected in those samples was set to 0% occupancy. Cells from a sampleof white blood cells incubated ex vivo with 1 μM (1) for 10 min prior toprobe treatment were set as 100% occupancy. The percent occupancy of allsamples was calculated relative to the vehicle group value, which wasset to 0% occupancy. See FIGS. 6-8, 12, 13, and 17.

Efficacy of (2) in PLP139-151 Induced EAE in SJL Mice (BTKi in aRelapsing Remitting Mouse Model of MS)

Compound 2 was administered prophylactically (starting day of induction)in PLP139-151 induced EAE in female SJL mice. at 3 mg/kg PO which hasbeen shown in the paper to be efficacious on RA models. Treatmentstarted on Day 0 post-induction: Vehicle, 0.3 mg/kg, 1.0 mg/kg, and 3mg/kg PO QD. The endpoints included a clinical score and body weight,receptor occupancy and CD69 expression at the end of the study (2 h and24 h post administration). FIGS. 9-11.

Animals: 90 Female SJL mice from Jax (10 weeks at arrival), at least 18gupon arrival.

Treatment Groups:

90 mice are induced with PLP/CFA/PTX. Prophylactic treatment starts onthe same day as EAE induction (before induction)

Group Treatment Dose Regimen Route N A SHAM n/a n/a n/a 3 B Vehicle n/aProphylactic, QD PO 15 C RN486 30 mpk Prophylactic, QD PO 15 D 2 0.3 mpkProphylactic, QD PO 15 E 2 1 mpk Prophylactic, QD PO 15 F 2 3 mpkProphylactic, QD PO 15 G FTY-720 1 mpk Prophylactic, QD PO 7 H Anti-CD20250 ug/mouse Prophylactic IV 5 (once on Day 0)

Induction of EAE in SJL Mice

PLP₁₃₉₋₁₅ was dissolved in PBS and emulsified with an equal volume ofCFA supplemented with 2 mg/mL mycobacterium tuberculosis (M.T.) (CFAalready has 1 mg/ml MT so another 1 mg/ml is added to a finalconcentration of 2 mg/ml). Mice were injected s.c. with 0.2 ml ofpeptide emulsion in the abdominal flank (0.1 ml on each side). On thesame day and 48 hr later, mice were injected i.p. with 200 μl (60 ng) ofBordetella Pertussis toxin in saline.

Solutions Preparation:

CFA Preparation: Total Volume needed: 10 mL; 2 mg/mL of M.T. was addedto IFA to get a total concentration of 2 mg/mL M.T. in CFA (add 100 mgM.T. to 50 mL of IFA).

PLP139-151 Preparation: 100 ug PLP₁₃₉₋₁₅₁: Concentration: 1 mg/mL; 15 mgof PLP in 15 mL PBS. PLP/CFA in a 1:1 ratio was emulsified usinghomogenizer method.

PTX Preparation: Stock Solution: Add 1 mL of PBS to the vial with 50 ug(store in fridge) 60 ng/mouse (0.2 mL/mouse)=0.3 ug/ml (dilute stock1:100, 150 ul in 25 mL PBS).

Efficacy of therapeutic treatment with BTKi in PLP139-151 induced EAE inSJL mice Compound 2 was administered therapeutically in PLP139-151induced EAE in female SJL mice. Dosing began on Day 9 post-induction:Vehicle, 1.0 mg/kg, 3 mg/kg, 10 mg/kg PO QD. The endpoints included aclinical score, receptor occupancy and CD69 expression at the end of thestudy (2 h and 24 hr post administration). FIGS. 14-16. A B-celldepleting antibody was used as a reference (anti-CD20).

Animals: 100 Female SJL mice from Jax (10 weeks at arrival), at least 18g upon arrival.

Treatment Groups:

100 mice were induced with PLP/CFA/PTX. At the first signs of diseasemice were randomized into different treatment groups according to theirclinical score.

Group Treatment Dose Regimen Route N A SHAM n/a n/a n/a 5 B Vehicle n/aTherapeutic, QD PO 15 C RN486 30 mpk Therapeutic, QD PO 15 D 2 1 mpkTherapeutic, QD PO 15 E 2 3 mpk Therapeutic, QD PO 15 F 2 10 mpkTherapeutic, QD PO 15 G Isotype 250 ug/mouse Therapeutic IV 10 HAnti-CD20 250 ug/mouse Therapeutic IV 10

Induction of EAE in SJL Mice

PLP₁₃₉₋₁₅ was dissolved in PBS and emulsified with an equal volume ofCFA supplemented with 2 mg/mL mycobacterium tuberculosis (M.T.) (CFAalready has 1 mg/ml MT so another 1 mg/ml is added to a finalconcentration of 2 mg/ml). Mice were injected s.c. with 0.2 ml ofpeptide emulsion in the abdominal flank (0.1 ml on each side). On thesame day and 48 hr later, mice were injected i.p. with 200 μl (60 ng) ofBordetella Pertussis toxin in saline.

Solutions Preparation:

CFA Preparation: Total Volume needed: 10 mL; Add 2 mg/mL of M.T. to IFAto get a total concentration of 2 mg/mL M.T. in CFA (add 100 mg M.T. to50 mL of IFA).

PLP139-151 Preparation: 100 ug PLP₁₃₉₋₁₅₁: Concentration: 1 mg/mL; 20 mgof PLP in 20 mL PBS; PLP/CFA was emulsified in a 1:1 ratio usinghomogenizer method.

PTX Preparation: Stock Solution: Add 1 mL of PBS to the vial with 50 ug(store in fridge) 60 ng/mouse (0.2 mL/mouse)=0.3 ug/ml (dilute stock1:100, 150 ul in 25 mL PBS).

PLP Induced EAE in SJL Mice

EAE (experimental autoimmune encephalomyelitis) is an animal model ofmultiple sclerosis (MS). This model reflects certain aspects of thepathology seen in MS including inflammation and demyelination. Compound2 was administered therapeutically in PLP139-151 induced EAE in femaleSJL mice. Dosing began on Day 17 post-induction: Vehicle, 1.0 mg/kg and10 mg/kg PO QD. The endpoint included a clinical score. FIGS. 18-19.Compound 2 was administered therapeutically in PLP139-151 induced EAE infemale SJL mice. Dosing began on Day 7 post-induction (before onset ofEAE): Vehicle, 1.0 mg/kg and 10 mg/kg PO QD.

The endpoint included a clinical score. FIG. 20-21.

Animals: Mice were female SJL mice from Jackson Laboratories. SJL micewere ordered at 8-10 weeks and used between 9-11 weeks. Animals werekept in the convention room of husbandry during the duration of theexperiment.

Procedure

1) PLP₁₃₉₋₁₅₁preparation: PLP₁₃₉₋₁₅₁ peptide solution was prepared atconcentration 1-2 mg/mL for in PBS.

2) IFA+MT preparation: OFA supplemented with M. tuberculosis H37RA wasprepared, as follows: IFA (10 mL/ampoule) was poured into a 50 ml Falcontube (50 mL for each 100 mg ampoule of desiccated TM H37RA). 100 mg ofTM H37RA was added into the 50 mL of CFA and homogenize briefly (˜1minute).

3) Emulsion preparation: Equal amounts of IFA/TM and PLP₁₃₉₋₁₅₁ was usedfor the emulsion. IFA/TM was added into a sterile beaker. The contentswere emulsified by adding the PLP₁₃₉₋₁₅₁ solution drop wise with atransfer pipette while homogenizing on low speed. After cooling on iceevery few minutes to prevent heating the emulsion (heating peptidesmight cause denaturation), PLP₁₃₉₋₁₅₁ solution was added and theprocedure was repeated until the emulsion had a smooth consistency. Theemulsion was homogenized on high-speed for a few seconds (15-30 seconds)to ensure a homogenous emulsion. The stability of the emulsion wastested by extruding a droplet onto the surface of 50 ml of PBS in areservoir or in a 100 ml beaker. The droplet of emulsion held togetherwithout dispersing. The emulsion was kept on ice until use.

4) PLP₁₃₉₋₁₅₁ injection: A 1 mL luerlok syringe was filled withemulsion. A 15 gauge animal feeding needle was added and the feedingneedle was dipped into the emulsion and the needle was filled. Whenneedle was filled, air was expelled from the syringe. Inject 0.2 ml ofPLP₁₃₉₋₁₅₁ emulsion in the abdominal flank of each mouse (0.1 ml at 2sites, close to the lymph nodes) using a 27 gauge needle.

5) PTX preparation: 1 mL of sterile PBS was added to 50 μg PTX (1 vial),and mixed gently. The stock was kept at 4° C. and a fresh solution fromthe stock was prepared for the injection at 48 h. Before use PTX wasdiluted with PBS to the desired concentration (0.25-1 ug/mL or 50-100ng/mouse).

6) PTX injection: SJL mice were injected with 200 ul i.p. using a 25gauge needle.

One injection was done on the same day as MOG35-55 injection andrepeated again 48 hours later.

7) Body Weight and Clinical Scoring: SJL mice were weighed and clinicalscore was assessed according to the scoring system at least 3times/week. At peak of disease (around day 10-15) they were scored everyday. The duration of study was up to 10 weeks.

1-20. (canceled)
 21. A method of treating multiple sclerosis (MS),comprising: administering to a subject in need thereof a therapeuticallyeffective amount of compound of the following formula:

or a pharmaceutically acceptable salt, a pharmaceutically acceptabletautomer, or a pharmaceutically acceptable stereoisomer thereof, whereinR¹═H or NH₂, R²═NH—CH₂—R³, NH—R⁴, or O—CH₂—R⁵; R³═N-cyclobutyl,pyrrolidine, or phenyl; R⁴=cyclohexyl, phenyl, or piperidine; andR⁵=pyrrolidine or piperidine.
 22. The method of claim 21, wherein the MSis selected from the group consisting of relapsing MS (RMS).relapsing-remitting MS (RRMS), progressive MS (PMS),secondary-progressive MS (SPMS), primary-progressive MS (PPMS), andprogressive-relapsing MS (PRMS).
 23. The method of claim 21, wherein theformula is the following:


24. The method of claim 21, wherein the formula is the following:


25. The method of claim 21, wherein the formula is the following:


26. The method of claim 21, wherein the formula is the following:


27. The method of claim 21, wherein the formula is the following:


28. The method of claim 21, wherein the formula is the following:


29. The method of claim 21, wherein the formula is the following:


30. The method of claim 21, wherein the formula is the following:


31. The method of claim 21, wherein the formula is the following:


32. The method of claim 21, wherein the formula is the following: